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Transcriptome Analysis Reveals the Importance of the Immune System During Early Pregnancy in Sheep

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Transcriptome Analysis Reveals the Importance of the Immune System During Early Pregnancy in Sheep bioRxiv preprint doi: https://doi.org/10.1101/673558; this version posted November 14, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Transcriptome analysis reveals the importance of the immune system during early pregnancy in sheep 1 Kisun Pokharel1, Jaana Peippo1, Melak Weldenegodguad1,2, Mervi Honkatukia3, Meng-Hua 2 Li4*, Juha Kantanen1* 3 1Natural Resources Institute of Finland (Luke), Jokioinen, Finland 4 2Department of Environmental and Biological Sciences, Faculty of Science and Forestry, University 5 of Eastern Finland, Kuopio, Finland 6 3NordGen – The Nordic Genetic Resources Center, Ås, Norway 7 4CAS Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese 8 Academy of Sciences (CAS), Beijing, China 9 * Correspondence: 10 Prof. Meng-Hua Li 11 [email protected] 12 Prof. Juha Kantanen 13 [email protected] 14 Keywords: Finnsheep, Texel, progesterone, immunoglobulins, Siglec, endogenous retrovirus, 15 endometrium, corpus luteum, prolificacy, preimplantation 16 Running title: Sheep preimplantation transcriptome 17 1 Abstract 18 The majority of pregnancy loss in ruminants occurs during the preimplantation stage, which is thus 19 the most critical period determining reproductive success. While ovulation rate is the major 20 determinant of litter size in sheep, interactions among the conceptus, corpus luteum and endometrium 21 are essential for pregnancy success. To evaluate the role of reproductive tract function in sheep 22 fertility, we performed a comparative transcriptome study by sequencing total RNA (mRNA and 23 miRNA) from corpus luteum (CL) and endometrium tissues collected during the preimplantation 24 stage of pregnancy in Finnsheep, Texel and F1 crosses. A total of 21,287 genes and 599 miRNAs 25 were expressed in our dataset. Ten out of the top 25 most highly expressed genes were shared across 26 tissues, indicating the complementary functions of the CL and endometrium. Moreover, highly 27 expressed autosomal genes in the endometrium and CL were associated with biological processes 28 such as progesterone formation (STAR and HSD3B1) in the CL and facilitation of maternal 29 recognition of pregnancy, trophoblast elongation and implantation (LGALS15, CST3, CST6, and 30 EEF1A1) in the endometrium. In the CL, a group of sialic acid-binding immunoglobulin (Ig)-like 31 lectins (Siglecs), solute carriers (SLC13A5, SLC15A2, SLC44A5) and chemokines (CCL5, CXCL13, 32 CXCL9) were upregulated in Finnsheep, while several multidrug resistance-associated proteins 33 (MRPs) were upregulated in Texel ewes. We also identified a novel ERV gene located in a reduced 34 FecL locus that is associated with sheep prolificacy and is upregulated in prolific Finnsheep. 35 Moreover, we report, for the first time in any species, several genes that are active in the CL during 36 early pregnancy (including SIGLEC13, SIGLEC14, SIGLEC6, MRP4, and CA5A). Importantly, 37 functional analysis of differentially expressed genes suggested that Finnsheep have a better immune bioRxiv preprint doi: https://doi.org/10.1101/673558; this version posted November 14, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International Sheeplicense. preimplantation transcriptome 38 system than Texel and that high prolificacy in Finnsheep might be governed by immune system 39 regulation. Taken together, the findings of this study provide new insights into the interplay between 40 the CL and the endometrium in gene expression dynamics during early pregnancy. The data and 41 results will serve as a basis for studying this highly critical period of pregnancy, which has wide 42 significance in mammalian fertility and reproduction. 43 2 Introduction 44 Litter size, a key determinant for the profitability of sheep production systems, is highly dependent 45 on ovulation rate and embryo development in the uterus. Earlier studies have shown that the trait of 46 high prolificacy can result due to the action of either a single gene with a major effect, as in the 47 Chinese Hu, Boorola Merino, Lacaune and small-tailed Han breeds (Mulsant et al., 2001; Souza et 48 al., 2001; Davis et al., 2002, 2006; Chu et al., 2007; Drouilhet et al., 2013), or different sets of genes, 49 as in the Finnsheep and Romanov breeds (Ricordeau et al., 1990; Xu et al., 2018). The Finnsheep or 50 Finnish landrace, one of the most highly prolific breeds, has been exported to more than 40 countries 51 to improve local breeds, although the heritability of ovulation rate is low (Hanrahan and Quirke, 52 1984). In recent years, a FecGF (V371M) mutation in gene GDF9 has been identified to be strongly 53 associated with litter size in Finnsheep and breeds such as the Norwegian White Sheep, Cambridge 54 and Belclare breeds, which were developed using Finnsheep (Hanrahan et al., 2004; Våge et al., 55 2013; Mullen and Hanrahan, 2014; Pokharel et al., 2018). 56 The success of pregnancy establishment in sheep and other domestic ruminants is determined at the 57 preimplantation stage and involves coordination among pregnancy recognition, implantation and 58 placentation, in which the corpus luteum (CL) and endometrium play vital roles (Geisert et al., 1992; 59 Spencer et al., 2004b, 2007). The preimplantation stage of pregnancy is the most critical period in 60 determining the litter size because of the high embryo mortality during this period. It has been shown 61 that most embryonic deaths occur before day 18 of pregnancy in sheep (Quinlivan et al., 1966; Bolet, 62 1986; Rickard et al., 2017). However, due to the biological complexity of the process and to technical 63 difficulties, embryo implantation is still not well understood. 64 The CL is an endocrine structure whose main function is to synthesize and secrete the hormone 65 progesterone. Progesterone production is essential for the establishment of pregnancy. However, if 66 pregnancy is not established, the CL will regress as a result of luteolysis, and a new cycle will begin. 67 The endometrium is the site of blastocyst implantation, but its function is not limited to implantation. 68 The outer lining of the endometrium secretes histotroph, a complex mixture of enzymes, growth 69 factors, hormones, transport proteins and other substances that are key to conceptus survival and 70 implantation, pregnancy recognition signal production and placentation (Spencer and Bazer, 2004; 71 Forde et al., 2013). In addition, the endometrium also plays an important role in regulating the 72 estrous cycle (Spencer et al., 2008). 73 The whole-transcriptome profiling approach enables a deeper understanding of the functions of both 74 the CL and endometrium, which may allow the identification of genes and markers that are 75 differentially expressed, for example, between breeds showing different litter size phenotypes. 76 Although most of the studies associated with early pregnancy have been performed in sheep (Spencer 77 et al., 2004b, 2007; Mamo et al., 2012; Bazer, 2013; Raheem, 2017), only a few studies have applied 78 transcriptomic approaches to the endometrium and CL. A microarray-based transcriptomic study 79 conducted by Gray et al. (2006) identified a number of endometrial genes regulated by progesterone 80 (from the CL) and interferon tau (IFNT; from the conceptus) in pregnant vs uterine gland knockout 81 (UGKO) ewes. In a more comprehensive study conducted by Brooks et al. (2016), transcriptome 2 This is a provisional file, not the final typeset article bioRxiv preprint doi: https://doi.org/10.1101/673558; this version posted November 14, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International Sheeplicense. preimplantation transcriptome 82 analysis of uterine epithelial cells during the peri-implantation period of pregnancy identified various 83 regulatory pathways and biological processes in sheep. Moore et al. (2016) combined gene 84 expression data with genome-wide association studies (GWASs) to understand the roles of CL and 85 endometrium transcriptomes in dairy cattle fertility. A study by (Kfir et al., 2018) identified 86 differentially expressed genes (DEGs) between Day 4 and Day 11 in the CL in cattle. Recently, a 87 study on endometrial gene expression differences between Finnsheep and European mouflon 88 identified several genes associated with reproductive processes (Yang et al., 2018). Though these 89 studies have certainly enhanced our understanding of the roles of the CL and endometrium during 90 early pregnancy and in ruminant fertility in general, none of the studies have conducted specific 91 comparisons between breeds with different reproductive potential. Thus, in this study, a comparison 92 of transcriptome profiles between two breeds was conducted to provide insight into the similarities in 93 developmental events in early pregnancy between the breeds. Using F1 crosses we were able to better 94 understand the heritability of the genetic markers. Here, the main goal of this study was to build a 95 global picture of transcriptional complexity in two tissues (Cl and endometrium) and examine 96 differences in developmental profiles during early pregnancy in sheep breeds showing contrasting 97 fertility phenotypes. Thus, this study has relevance to sheep breeding towards achieving improved 98 reproductive capacity. 99 3 Materials and Methods 100 3.1 Experimental design 101 All procedures for the experiment and sheep sampling were approved by the Southern Finland 102 Animal Experiment Committee (approval no. ESAVI/5027/04.10.03/2012). The animals were kept at 103 Pusa Farm in Urjala, located in the province of Western Finland, during the experimental period.
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